Transdermal compositions for anticholinergic agents

ABSTRACT

The present invention relates generally to compositions or formulations for transdermal or transmucosal administration of anticholinergic agents such as oxybutynin. The invention utilizes a novel delivery vehicle and is a substantially malodorous-free and irritation free transdermal formulation which is substantially free of long chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters. A method is disclosed for treating a subject for urinary incontinence with these formulations while reducing the incidences of peak concentrations of drug and undesirable side effects associated with oral anticholinergics.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is (1) a continuation-in-part of application Ser. No.10/798,111 filed Mar. 10, 2004, and (2) a continuation-in-part ofapplication Ser. No. 11/755,923 filed May 31, 2007, which is acontinuation-in-part of U.S. patent application Ser. No. 11/371,042filed Mar. 7, 2006, now U.S. Pat. No. 7,335,379, which is a continuationof International application no. PCT/EP2004/011175 filed Oct. 6, 2004,which claims the benefit of U.S. provisional patent application No.60/510,613, filed Oct. 10, 2003. The '923 application is also acontinuation-in-part of U.S. patent application Ser. No. 11/634,005filed Dec. 4, 2006, now U.S. Pat. No. 7,404,965, which is a continuationof application Ser. No. 10/343,570 filed May 19, 2003, now U.S. Pat. No.7,214,381, which is the U.S. national stage of International applicationno. PCT/EP01/09007 filed Aug. 3, 2001. The '111 application claimspriority to U.S. provisional patent application 60/510,613 filed Oct.10, 2003 and U.S. provisional patent application 60/453,604 filed Mar.11, 2003. Each prior application is expressly incorporated herein in itsentirety by reference thereto.

TECHNICAL FIELD

This invention relates generally to formulations for the transdermaldelivery of anti-cholinergic agents, typically oxybutynin, and moreparticularly to topical formulations of oxybutynin that contain a noveldelivery vehicle and that are substantially free of long chain fattyalcohols, long chain fatty acids, and long-chain fatty esters.

This invention also relates to methods for treating overactive bladderand urinary incontinence using such formulations.

BACKGROUND OF THE INVENTION

Topical or transdermal delivery systems for the administration of drugsare known to offer several advantages over oral delivery of the samedrugs. Generally, the advantages of topical or transdermal delivery ofdrugs relate to pharmacokinetics. More specifically, one common problemassociated with the oral delivery of drugs is the occurrence of peaks inserum levels of the drug, which is followed by a drop in serum levels ofthe drug due to its elimination and possible metabolism. Thus, the serumlevel concentrations of orally administered drugs have peaks and valleysafter ingestion. These highs and lows in serum level concentrations ofdrug often lead to undesirable side effects.

In contrast, topical and transdermal delivery of drugs provides arelatively slow and steady delivery of the drug. Accordingly, unlikeorally administered drugs, the serum concentrations of topically ortransdermally delivered drugs are substantially sustained and do nothave the peaks associated with oral delivery.

The sustained serum concentrations associated with topical ortransdermal drug delivery avoids the systemic side effects of oraladministration of drugs. Specifically, first pass metabolism of the drugby the liver is circumvented by utilizing transdermal or topicaldelivery vehicles for the administration of drugs.

For example, there is a significant decrease in adverse effectsassociated with the transdermal delivery of oxybutynin. Oxybutynin is anantispasmodic, anticholinergic agent. Oxybutynin is administered as aracemate of R- and S-isomers. Chemically, oxybutynin is d,l (racemic)4-diethylamino-2-butynyl phenylcyclohexylglycolate. The empiricalformula of oxybutynin is C₂₂H₃₁NO₃. Oxybutynin has been found to have adirect antispasmodic effect on smooth muscle and inhibits the muscarinicaction of acetylcholine on smooth muscle, but exhibits only one-fifth ofthe anticholinergic activity of atropine detrusor muscle (effectobserved in rabbits), and four to ten times its antispasmodic activity.Oxybutynin has not been found to possess blocking effects at skeletalneuromuscular junctions or autonomic ganglia (antinicotinic effects).Moreover, oxybutynin has been found to relax bladder smooth muscle.

In patients with conditions characterized by involuntary bladdercontractions, cystometric studies have demonstrated that oxybutyninincreases bladder (vesical) capacity, diminishes the frequency ofuninhibited contractions of the detrusor muscle, and delays the initialdesire to void. Oxybutynin thus decreases urgency and the frequency ofboth incontinent episodes and voluntary urination. It has also beenreported that antimuscarinic activity resides predominantly in theR-isomer. Oral oxybutynin is widely used for the relief of symptoms ofbladder instability associated with voiding in patients with uninhibitedneurogenic or reflex neurogenic bladder, i.e., urgency, frequency,urinary leakage, urge incontinence, and dysuria.

Until recently oral anticholinergic medications have been the primarypharmacotherapy for the treatment of urge urinary incontinence andoveractive bladder (OAB), among which oxybutynin is the golden standardmedication. There are several different drug products available on theinternational market for oral administration of oxybutynin, includingimmediate- and extended-release formulations. Both have been shown to beeffective in the treatment of OAB. However, their compliance has beenlimited by anticholinergic side effects. Adverse reactions associatedwith oxybutynin therapy, however, may include cardiovascularmanifestations such as palpitations, tachycardia or vasodilatation;dermatologic manifestations such as decreased sweating, rash;gastrointestinal and genitourinary manifestations such as constipation,decreased gastrointestinal motility, dry mouth, nausea, urinaryhesitance and retention; nervous system manifestations such as asthenia,dizziness, drowsiness, hallucinations, insomnia, restlessness; opthalmicmanifestations such as amblyopia, cycloplegia, decreased lacrimation,mydriasis. Most common side effects associated with oral oxybutyninencompasses dry mouth, dizziness, blurred vision, and constipation.These adverse experiences may be uncomfortable enough to substantiallylimits long-term patient compliance (<18% at 6 months). Oralformulations of oxybutynin indeed undergo hepatic metabolism to formN-desethyloxybutynin (DEO), which is considered to be the primaryunderlying cause of dry mouth associated with anticholinergic therapy.See Appell R. A., Chancellor M. B., Zobrist R. H., Thomas H., Sanders S.W., “Pharmacokinetics, metabolism, and saliva output during transdermaland extended-release oral oxybutynin administration in healthysubjects”, Mayo Cline Proc. 78: 696-702; 2003, the entire content ofwhich is herein incorporated as reference. See also Kelleher C. J.,Cardozo L. D., Khullar V., Salvatore S., “A medium-term analysis of thesubjective efficacy of treatment for women with detrusor instability andlow bladder compliance.”, Br J Obstet Gynaecol. 104: 988-93; 1997, theentire content of which is herein incorporated as reference.

The development of an extended-release formulation of oxybutynin wasintended to preserve the efficacy of the drug while reducing theincidence and severity of dry mouth and other anticholinergic sideeffects. Extended-release formulations allow once-a-day dosing andprovide a more consistent therapeutic drug level in the blood throughoutthe day and less metabolite generation. This lower DEO metabolitegeneration is associated with reduced adverse effects. Recently, atransdermal patch of oxybutynin (OXYTROL®, Watson Pharmaceuticals, Inc.)has entered the marketplace as a therapeutic option for OAR Transdermaladministration of oxybutynin leads to clinically important changes inthe pharmacokinetics, metabolism, and pharmacodynamic effects ofoxybutynin compared with extended-release oral treatment. Transdermaladministration of oxybutynin, as any other route of administrationavoiding gastrointestinal and hepatic first-pass metabolism, results inlower fluctuation in oxybutynin plasmatic levels, in reduced DEOmetabolite formation, and in increased saliva production. Lower DEOplasma concentrations and greater saliva output are thought tocorrespond to the reported low incidence of dry mouth in patientstreated with transdermal oxybutynin. See, Dmochowski R R, Davila G W,Zinner N R, Gittelman M C, Saltzstein D R, Lyttle S, Sanders S W; ForThe Transdermal Oxybutynin Study Group.; “Efficacy and safety oftransdermal oxybutynin in patients with urge and mixed urinaryincontinence”, The Journal of Urology, Vol. 168, 580-586, August 2002,the entire content of which is herein incorporated as reference. PhaseIII studies comparing OXYTROL® patch to oral extended-release tablet(DITROPAN® XL, Ortho McNeil Janssen) showed that only 4.1% of thepatients on transdermal therapy reported dry mouth, whereas 60.8% of thepatients on oral treatment reported this side effect. This reduction ofincidence of dry mouth, together with the improvement of overactivebladder symptoms, is responsible for a better quality of life seen inpatients treated with transdermal oxybutynin compared to oral oxybutynintherapy. Thus, it can be easily seen that transdermal delivery ofoxybutynin has been shown to be more advantageous, as well as preferredover oral delivery of oxybutynin.

However, although the transdermal and/or transmucosal delivery ofoxybutynin overcome some of the problems associated with oraladministration of oxybutynin, such as that described above, this routeof administration is not free of its own drawbacks. Transdermal patchesvery often cause allergic reactions and skin irritations due to theirocclusive nature, or due to their composition (incompatibility reactionswith the polymers used). In the OXYTROL® phase III study, 16.8% of thepatients reported itching at the patch application site as an adverseeffect. A transdermal oxybutynin gel should combine the advantages ofthe transdermal route (reduced side effects related avoidance offirst-pass metabolism leading to lowered formation of DEO metabolite;steady plasmatic levels) with a low potential for skin irritation. Sincean oxybutynin gel would be applied directly to the skin, skin reactionsassociated with the adhesive properties and the occlusive nature oftransdermal patch formulations (e.g. OXYTROL®) should be avoided.

Besides skin irritation and tolerance considerations, another issue oftransdermal drug delivery systems is that these systems are typicallyrestricted to low-molecular weight drugs and those with structureshaving the proper lipophilic/hydrophilic balance. High molecular weightdrugs, or drugs with too high or too low hydrophilic balance, oftencannot be incorporated into current transdermal systems inconcentrations high enough to overcome their impermeability through thestratum corneum. Efforts have been made in the art to chemically modifythe barrier properties of skin to permit the penetration of certainagents (since diffusion is primarily controlled through the stratumcorneum), enhance the effectiveness of the agent being delivered,enhance delivery times, reduce the dosages delivered, reduce the sideeffects from various delivery methods, reduce patient reactions, and soforth. In this regard, penetration enhancers have been used to increasethe permeability of the dermal surface to drugs. Various permeationenhancers have been reported as being effective for the transdermal ortopical delivery of oxybutynin. For example, U.S. Pat. Nos. 5,411,740,5,500,222, and 5,614,211, each disclose monoglyceride or a mixture ofmonoglycerides of fatty acids as the preferred permeation enhancer foran oxybutynin transdermal therapeutic system. U.S. Pat. No. 5,736,577describes a pharmaceutical unit dosage form for transdermaladministration of (S)-oxybutynin comprising a permeation enhancer. U.S.Pat. Nos. 5,834,010 and 6,555,129 both disclose triacetin as apermeation enhancer for oxybutynin. U.S. Pat. No. 5,747,065 disclosesmonoglycerides and esters of lactic acid as a permeation enhancingmixture for oxybutynin. U.S. Pat. No. 5,843,468 describes a dualpermeation enhancer mixture of lauryl acetate and a glycerol monolauratefor transdermal administration of oxybutynin. U.S. Pat. No. 6,004,578disclose permeation enhancers selected from the group consisting ofalkyl or aryl carboxylic acid esters of polyethyleneglycol monoalkylether, and polyethyleneglycol alkyl carboxymethyl ethers for atransdermal matrix drug delivery device comprising oxybutynin.Meanwhile, U.S. Pat. No. 6,267,984 discloses skin permeation enhancercompositions comprising a monoglyceride and ethyl palmitate fortransdermal delivery of oxybutynin. U.S. Pat. No. 6,562,368 disclosesthe use of hydroxide-releasing agent to increase the permeability ofskin or mucosal tissue to transdermally administered oxybutynin. U.S.Pat. Nos. 7,029,694 and 7,179,483 relate to oxybutynin gel formulationsthat include permeation enhancers as optional components, among whichtriacetin and monoglycerides are preferred permeation enhancers.

The most common penetration enhancers, however, are toxic, irritating,oily, odiferous, or allergenic. Specifically, the penetration enhancersused and thought to be necessary to transdermally deliver oxybutynin,namely, long-chain acids such as lauric acid and oleic acid, long-chainalcohols such as lauryl or myristyl alcohol, and long-chain esters suchas triacetin (the glycerol trimester of acetic acid), glycerolmonolaurate or glycerol monooleate, tend to include aliphatic groupsthat make the formulations oily and malodorous.

Thus, there is a need in the industry for a transdermal formulation thatadequately delivers oxybutynin to patients with skin tolerability, butdoes not include the unpleasant odor common to the prior artformulations.

SUMMARY OF INVENTION

The present invention relates to transdermal or transmucosalmalodorous-free and irritation-free formulations comprising oxybutyninand a delivery vehicle. In particular, the formulation comprises ananti-cholinergic agent of oxybutynin; and a delivery vehicle whichcomprises a C2 to C4 alkanol, a polyalcohol, and a monoalkyl ether ofdiethylene glycol present in relative amounts sufficient to providepermeation enhancement of oxybutynin through mammalian dermal or mucosalsurfaces. The formulation is substantially free of long-chain fattyalcohols, long-chain fatty acids and long-chain fatty esters in order toavoid potential undesirable odor and irritation effects caused by suchcompounds during use of the formulation. Thus, advantageously, theformulations of the present invention do not include the undesirableodor-causing and irritation-causing permeation enhancers that were oncethought to be necessary for such transdermal or transmucosalformulations.

In accordance with the invention, the alkanol may be present in anamount between about 45% to 75% by weight of the vehicle. The alkanolmay be ethanol, isopropanol, n-propanol, and mixtures thereof.Preferably, the alkanol is ethanol. The polyalcohol may beadvantageously present in an amount between about 1% and 30% by weightof the vehicle. The polyalcohol may be polyethylene glycols havinggeneral formula CH₂OH(CH₂OH)_(n)CH₂OH wherein the number of oxyethylenegroups represented by n is between 4 to 200, propylene glycol,dipropylene glycol, butylene glycol, hexylene glycol, glycerin, andmixtures thereof. Preferably, the polyalcohol is propylene glycol. Themonoalkyl ether of diethylene glycol may be present in an amount ofabout 1% and 15% by weight of the vehicle. The monoalkyl ether ofdiethylene glycol may be diethylene glycol monoethyl ether, diethyleneglycol monomethyl ether, and mixtures thereof. Preferably, the monoalkylether of diethylene is diethylene glycol monoethyl ether. In accordancewith the invention, oxybutynin may be present in an amount between about0.1% to 20% by weight of the vehicle. Oxybutynin may be present as thefree base or as a pharmaceutically acceptable salt thereof. Examples ofsalt comprise, but are not limited to, acetate, bitartrate, citrate,edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, hydrobromide, hydrochloride, lactate, malate, maleate,mandelate, mesylate, methylnitrate, mucate, napsylate, nitrate, pamoate,pantothenate, phosphate, salicylate, stearate, succinate, sulfate,tannate and tartrate. Preferably, oxybutynin is present as free base oras the hydrochloride salt. If desired, oxybutynin may be present incombination with a secondary active agent for concurrent administrationsubject to the previously stated provision.

The formulation can further include at least one of a gelling agent,neutralizing agent, buffering agent, moisturizing agent, humectant,surfactant, antioxidant, emollient, film-forming agent, or buffer, andthe like.

The formulation may be applied directly to the skin such as by, forexample and not limitation, a gel, a foam, an ointment, a liposomalemulsion, a microemulsion, a nanoemulsion, a suspension, or a lacquerand the like, or other passive or active transdermal devices forabsorption through the skin or mucosal surface. In a preferred aspect ofthe invention, the formulation is a gel.

The present invention further provides a method for treating overactivebladder or urge and urinary incontinence in a subject, the methodcomprising administering to a subject in need thereof, a topical ortransdermal composition of oxybutynin according to the presentinvention.

Advantageously, the composition of the present invention provides asteady plasma concentration of oxybutynin to a subject administered withthe composition, as well as avoiding undesirable peaks in drugconcentration, and/or reduces the incidences of unwanted, undesirableside effects such as dry mouth, accommodation disturbances, nausea anddizziness.

The oxybutynin composition of the present invention provides a sustainedtransdermal oxybutynin flux allowing therapeutic levels of oxybutyninfor at least 24 hours, preferably for at least 48 hours and mostpreferably for at least 72 hours. Thus, the composition only needs to beadministrated once per day, once every other day, once every third dayor twice per week.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the results from an in-vitro 24-hourcomparative permeation study comparing permeation of a compositioncomprising oxybutynin of the present invention, and a marketed product.

FIG. 2 is a graph illustrating the drug flux profiles of thecompositions of FIG. 1.

FIG. 3 is a graph illustrating the results from an in-vitro 24-hourcomparative permeation study comparing permeation of two compositionscomprising oxybutynin of the present invention, and a marketed product.

FIG. 4 is a graph illustrating the drug flux profiles of thecompositions of FIG. 3.

FIG. 5 is a graph illustrating the results from an in-vitro 24-hourcomparative permeation study comparing permeation of two compositionscomprising oxybutynin out of the scope of the present invention, and amarketed product.

FIG. 6 is a graph illustrating the drug flux profiles of thecompositions of FIG. 5.

FIG. 7 is a graph illustrating the results from an in-vitro 24-hourcomparative permeation study comparing permeation of a compositioncomprising oxybutynin of the present invention, and two compositionscomprising oxybutynin out of the scope of the present invention.

FIG. 8 is a graph illustrating the drug flux profiles of thecompositions of FIG. 7.

FIG. 9 is a graph illustrating the results from an in-vitro 24-hourcomparative permeation study comparing permeation of a compositioncomprising oxybutynin of the present invention, and two compositionscomprising oxybutynin out of the scope of the present invention.

FIG. 10 is a graph illustrating the drug flux profiles of thecompositions of FIG. 9.

FIG. 11 is a graph illustrating the results from an in-vitro 24-hourcomparative permeation study comparing permeation of three compositionscomprising oxybutynin out of the scope of the present invention.

FIG. 12 is a graph illustrating the drug flux profiles of thecompositions of FIG. 11.

FIG. 13 is a graph illustrating the plasmatic concentrations ofoxybutynin in healthy volunteers during the pilot pharmacokinetic studyof an oxybutynin gel formulation of the present invention.

FIG. 14 is a graph illustrating the plasmatic concentrations ofN-desethyloxybutynin in healthy volunteers during the pilotpharmacokinetic study of an oxybutynin gel formulation of the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention relates generally to compositions or formulationsthat contain an anti-cholinergic agent, preferably oxybutynin, foradministration to subjects in need thereof. The invention furtherrelates to formulations for the transdermal or transmucosaladministration of oxybutynin that are substantially free of malodorous,and irritation-causing permeation enhancers. Surprisingly, theformulation of the present invention can achieve sufficient absorptionto result in an effective dosage of oxybutynin circulating in serumwithout the inclusion of the malodorous and irritation-causingpermeation enhancers that have been used to date. In a preferred aspectof the invention, the formulation is a clear, water-washable,quick-drying, spreadable, non-greasy, non-occlusive topical gel ofoxybutynin which is free of fatty permeation enhancers.

Advantageously, the substantial omission of the long-chain fattyalcohols, long-chain fatty acids, and long-chain fatty esters provides aformulation that does not have the unpleasant odor, irritation, and/orgreasy texture caused by formulations of the prior art that include oneor more of such compounds. Thus, the formulation in accordance with thepresent invention will result in greater patient compliance. Theinventive formulations are substantially free of such alcohols, acids,and esters so that the odors associated with those compounds do notemanate from the formulation. In this regard, “substantially free” meansan amount which does not impart a perceptible odor to the formulation ata distance of one meter. Such formulations are also deemed to besubstantially odor-free. For the purpose of example and illustration, aformulation comprising fatty alcohols, fatty acids and/or fatty estersin an amount of less than about 0.1% by weight of the formulation issubstantially odor-free.

In accordance with the invention, oxybutynin is present as the free baseor as a salt. For purpose of illustration but not limitation, examplesof some pharmaceutically acceptable salts of oxybutynin are acetate,bitartrate, citrate, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, hydrobromide, hydrochloride, lactate,malate, maleate, mandelate, mesylate, methylnitrate, mucate, napsylate,nitrate, pamoate, pantothenate, phosphate, salicylate, stearate,succinate, sulfate, tannate and tartrate. The oxybutynin may be presentas a racemate, as a pure single isomer, or as a mixture of S enantiomerand R enantiomers. Pharmaceutical derivatives of oxybutynin which areclose-related to oxybutynin are also understood to fall within the scopeof the present invention.

In accordance with the invention, the delivery vehicle of the presentinvention preferably comprises a C2 to C4 short-chain alkanol, apolyalcohol, and a monoalkyl ether of diethylene glycol in an amountsufficient to provide permeation enhancement of the oxybutynin throughmammalian dermal or mucosal surfaces. For the purpose of illustrationand not limitation, the alkanol may be ethanol, isopropanol, orn-propanol. The alkanol is preferably ethanol. The alkanol is present inan amount between about 45 to 75% w/w, preferably between about 50% to70%, and more preferably between about 55% and 65% w/w. As known in theart, the amount of the alkanol may be selected to maximize the diffusionof the active agent through the skin while minimizing any negativeimpact on the active agent itself or desirable properties of theformulation. The alkanol can be present in a mixture with water. Thepolyalcohol is advantageously present in an amount between about 1% and30% of the vehicle, preferably from 2.5% to 20% w/w, and more preferablyfrom about 5% to 10% w/w. The monoalkyl ether of diethylene glycol ispresent in an amount of about 1% and 15%, preferably between about 2.5%to 10% w/w and more preferably between about 2.5% to 5% w/w.

The formulation may further include a thickening agent or gelling agentpresent in an amount sufficient to alter the viscosity of theformulation. A gelling agent can be selected from the group including:carbomer 980 or 940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF,ETD 2020, 2050, 934P NF, 971P NF, 974P NF, Noveon AA-1 USP; cellulosederivatives such as ethylcellulose, hydroxypropylmethylcellulose(1-IPMC), ethylhydroxyethylcellulose (EHEC), carboxymethylcellulose(CMC), hydroxypropylcellulose (HPC) (Klucel grades),hydroxyethylcellulose (HEC) (Natrosol grades), HPMCP 55, Methocelgrades; natural gums such as arabic, xanthan, guar gums, alginates;polyvinylpyrrolidone derivatives such as Kollidon grades;polyoxyethylene polyoxypropylene copolymers such as Lutrol F grades 68,127. Other gelling agents include chitosan, polyvinyl alcohols, pectins,veegum grades. A tertiary amine, such as triethanolamine or trolamine,can be included to thicken and neutralize the system. The amount and thetype of the gelling agent in the formulation may be selected by the manskilled in the art to provide the desired product consistency and/orviscosity to facilitate application to the skin. The gelling agent ispresent from about 0.2 to about 30% w/w of the formulation depending onthe type of polymer. For example, the gelling agent is preferablypresent in an amount between about 0.3% to 2% for carbomers, and betweenabout 1% to 5% for hydroxypropylcellulose derivatives.

The formulation may further include preservatives such as, but notlimited to, benzalkonium chloride and derivatives, benzoic acid, benzylalcohol and derivatives, bronopol, parabens, centrimide, chlorhexidine,cresol and derivatives, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric salts, thimerosal, sorbic acid, derivativesthereof and the like. The preservative is present from about 0.01 toabout 10% w/w depending on the type of compound.

The formulation may further include antioxidants such as but not limitedto, tocopherol, ascorbic acid, butylated hydroxyanisole, butylatedhydroxytoluene, fumaric acid, malic acid, propyl gallate, sulfites,derivatives thereof and the like. The antioxidant is present from about0.001 to about 5.0% w/w of the formulation depending on the type ofcompound.

The formulation may further include a buffer such as carbonate buffers,citrate buffers, phosphate buffers, acetate buffers, hydrochloric acid,lactic acid, tartric acid, diethylamine, triethylamine,diisopropylamine, aminomethylamine. Although other buffers as known inthe art may be included. The buffer may replace up to 100% of the wateramount within the formulation.

The formulation may further include a humectant. The formulation mayfurther include humectant, such as but not limited to glycerin,propylene, glycol, sorbitol, triacetin. The humectant is present fromabout 1 to 10% w/w of the formulation depending on the type of compound.

The formulation may further include a sequestering agent such as edeticacid. The sequestering agent is present from about 0.001 to about 5% w/wof the formulation depending on the type of compound.

The formulation may further include anionic, non-ionic or cationicsurfactants. The surfactant is present from about 0.1% to about 30% w/wof the formulation depending on the type of compound.

The formulation may further include a pH regulator, generally, aneutralizing agent, which can optionally have cross-linking function. Byway of example and not limitation, the pH regulator may include aternary amine such as monoethanolamine, diethanolamine, triethanolamine,tromethamine, tetrahydroxypropylethylendiamine, aminomethyl propanol,diisopropanolamine, or an inorganic alkali such as NaOH solution, KOHsolution, or NH₄OH solution. The pH regulator is present in theformulations in variable amounts depending on the nature and therelative strength of the pH regulator. The optimum pH may also bedetermined and may depend on, for example, the nature of the activeagent and the degree of flux required.

The formulation may further include moisturizers and emollients tosoften and smoothen the skin or to hold and retain moisture. By way ofexample and not limitation, moisturizers and emollients may includecholesterol, lecithin, light mineral oil, petrolatum, and urea.

For any particular formulation, the active agent of oxybutynin and otheringredients may be selected to achieve the desired drug delivery profileand the amount of penetration desired.

Although oxybutynin is the preferred anti-cholinergic agent that isdisclosed herein, other such agents, among which those having anantimuscarinic activity are preferred, can be used in place ofoxybutynin. Preferred anti-cholinergic drugs with antimuscarinicactivity include, without limitation, tolterodine, trospium,propiverine, flavoxate, emepronium, propantheline, darifenacin, andsolifenacin.

In a preferred embodiment, the composition is provided as a topical,non-occlusive gel. In particular, the composition comprises oxybutyninfree base in an amount of about 3% by weight of the composition; and thedelivery system comprises anhydrous ethanol in an amount of about 50.72%by weight of the composition, propylene glycol in an amount of about 20%by weight of the composition, monoethyl ether of diethylene glycol in anamount of about 2.5% by weight of the composition, hydrochloric acid toprovide a pH of about 6 to 9, hydroxypropylcellulose in an amount ofabout 1 to 2% by weight of the composition, butylhydroxytoluene in anamount of about 0.05% by weight of the composition, and water quantumsufficit. Alternatively, the composition can include oxybutynin as ahydrochloride salt in an amount between about 5 to 15% by weight of thecomposition; and the delivery system comprises ethanol, isopropanol, ora mixture thereof in an amount between about 50 to 70% by weight of thecomposition; propylene glycol in an amount between about Ito 10% byweight of the composition; a monoethyl ether of diethylene glycol in anamount between about 1 to 5% by weight of the composition, and water.Preferably, the composition is administered to a patient in need thereofby the means of a metered-dose dispenser. Between 1 and 5 grams istypically applied over a skin surface of 100 to 1500 cm² and preferablybetween about 2.5 grams and 3.0 grams of gel is applied over a skinsurface of about 500 to 1000 cm².

Another preferred composition comprises a gel composition of oxybutyninhydrochloride in an amount of about 10% by weight of the composition;and the delivery system comprises anhydrous ethanol in an amount ofabout 60% by weight of the composition, propylene glycol in an amountbetween about 1 to 10% by weight of the composition, monoethyl ether ofdiethylene glycol in an amount between about 1 to 5% by weight of thecomposition, sodium hydroxide to provide a pH of about 4 to 7,hydroxypropylcellulose in an amount of about 1 to 2% by weight of thecomposition, butylhydroxytoluene in an amount between about in an amountof about 0 to 0.05% by weight of the composition, and water quantumsufficit. About 0.5 to 2 grams of this composition is dispensed from amultiple-dose container; and applied over a skin surface between 50 and500 cm², preferably 1 gram of gel is applied over a skin surface ofabout 150 to 350 cm².

The invention also relates to a method for administering oxybutynin to amammal in need thereof comprising topically or transdermallyadministering to the skin or the mucosa of a mammal one of thecompositions disclosed herein. Preferably, the mammal is a human. Forexample, the treatments methods include treating hyperactivity of thedetrusor muscle with frequent urge to urinate, increased urinationduring the night, urgent urination, involuntary urination with orwithout the urge to urinate, painful or difficult urination, detrusorhyperreflexia and detrusor instability. Typically, not more than 200 mgof oxybutynin is administered per day, with a daily dose of oxybutyninbetween about 40 and about 100 mg being preferred. The composition isadvantageously administered upon the abdomen, shoulder, arm, or thigh ofthe subject.

A more preferred daily dosage of oxybutynin is between 0.06 and 0.18 mcgper cm² and is dispensed from a unidose container or from amultiple-dose container for a duration of from about 24 to about 72hours. The application of the composition may be made on the same or adifferent site on consecutive days. Advantageously, the application ofthe composition is rotated between shoulder, thigh, abdomen, and arm onconsecutive days.

In certain preferred embodiments of the present invention, theformulation may have the following formulae as shown in Tables 1 to 4herein.

TABLE 1 Oxybutynin (expressed as free base) 0.1-20% w/w Short-chainalkanol 45-75% w/w Polyalcohol 1-30% w/w Diethylene glycol mono alkylether 1-15% w/w Thickening agent 0.2-30% w/w pH adjusting agent qs pH4-9 Purified water q. ad. 100% w/w

TABLE 2 Oxybutynin free base 1-10% w/w Ethanol (expressed as absolute)45-75% w/w Propylene glycol 1-30% w/w Diethylene glycol mono ethyl ether1-15% w/w Carbomer 0.3-2% w/w pH adjusting agent qs pH 5-8 Purifiedwater q. ad. 100% w/w

TABLE 3 Oxybutynin free base 1-10% w/w Ethanol (expressed as absolute)45-75% w/w Propylene glycol 1-30% w/w Diethylene glycol mono ethyl ether1-15% w/w Hydroxypropylcellulose 0.5-2% w/w pH adjusting agent qs pH 5-8Purified water q. ad. 100% w/w

TABLE 4 Oxybutynin Hydrochloride 5-15% w/w Ethanol (expressed asabsolute) 45-75% w/w Propylene glycol 1-30% w/w Diethylene glycol monoethyl ether 1-15% w/w Hydroxypropylcellulose 0.5-2% w/w pH adjustingagent qs pH 5-8 Purified water q. ad. 100% w/w

The formulation of the present invention is advantageous at least forthe following reasons. First, the formulations of the present inventionare substantially free of long-chain fatty alcohols, long-chain fattyacids, and long-chain fatty esters. Surprisingly, the formulationsexhibit skin penetration sufficient to deliver an effective dosage ofoxybutynin to the user. This is an unexpected advantage that those ofordinary skill in the art would not have readily discovered since it hadbeen generally understood that permeation enhancers, and moreparticularly long-chain fatty alcohols, long-chain fatty acids, and longchain fatty esters, would be required to enhance skin penetration ofoxybutynin to permit an effective dose to penetrate the skin. Second,because the formulation does not include aliphatic acid groups, such asfatty acids, that are commonly included in topical gels, it does nothave the odor or oily texture which is associated with that ingredientas in presently-available gels. Numerous studies acknowledge theirritation-causing potential of unsaturated fatty acids such as oleicacid. See, Tanojo H. Boelsma E, Junginger H E, Ponce M, Bodde H E, “Invivo human skin barrier modulation by topical application of fattyacids,” Skin Pharmacol Appl. Skin Physiol. 1998 March April; 11 (2) 8797. Third, the absence of long-chain fatty alcohols, long-chain fattyacids, and long-chain fatty esters means that the irritation potentialis lower and that there is less chance for the components to interact,reducing the need for stabilizers in the formulation. It is to beunderstood, however, that if such stabilizers are desired, the inventionencompasses formulations which include antioxidants, chelators orpreservatives. The reduction in the number of ingredients isadvantageous at least in reducing manufacturing costs, possible skinirritation. Additionally, the reduced number of ingredients increasesthe storage stability of the formulation by decreasing the chance thatthe ingredients will interact prior to being delivered to the patient inneed thereof. This does not, however, imply that additional ingredientscannot be included in the formulation for particular aesthetic and/orfunctional effects. For example, the formulation may optionally includeone or more moisturizers for hydrating the skin or emollients forsoftening and smoothing the skin. Glycerin is an example of such asuitable moisturizing additive.

The formulation may be applied once daily, or multiple times per daydepending upon the condition of the patient. The formulation of theinvention may be applied topically to any body part, such as the thigh,abdomen, shoulder, and upper arm. In one embodiment, up to 10 grams of aformulation in the form of a gel is applied to an area of skin. In apreferred embodiment of the invention, not more than 5 grams of aformulation in the form of a gel is applied to about an area of skin forabout 1 g of gel. In a most preferred embodiment of the invention, about1 to 3 grams of a formulation in the form of a gel is applied to about a100 square-centimeter to a 1000 square-centimeter area of skin.Formulation of the present invention may be applied on alternate areasof the body as applications alternate. For example, the gel may beapplied to the abdomen for the first application, the upper arm for thesecond application, and back to the abdomen for the third application.This may be advantageous in alleviating any sensitivity of the skin torepeated exposure to components of the formulation. Alternatively, theformulation of the present invention may be applied always on the samearea of the body.

The invention includes the use of the formulations described above totreat subjects to increase circulating levels of oxybutynin within thepatient. Preferred dosage units are capable of delivering an effectiveamount of oxybutynin over a period of about 24 hours. By an “effective”or “therapeutically effective” amount of oxybutynin is meant a nontoxic,but sufficient amount of oxybutynin to provide the desired effect.However, it will be appreciated by those skilled in the art that thedesired dose will depend on the specific form of oxybutynin as well ason other factors; the minimum effective dose of each form of oxybutyninis of course preferred to minimize the side effects associated treatmentwith oxybutynin. The formulation is preferably applied on aregularly-timed basis so that administration of oxybutynin issubstantially continuous.

The composition may be applied directly or indirectly to the skin ormucosal surfaces. Preferably, the composition is non occlusive. Thephrase “non-occlusive” as used herein refers to a system that does nottrap nor segregate the skin from the atmosphere.

The composition of the invention can be in a variety of forms suitablefor transdermal or transmucosal administration. For purpose ofillustration and not limitation, the various possible forms for thepresent composition include gels, ointments, creams, lotions,microspheres, liposomes, micelles, foams, lacquers, non-occlusivetransdermal patches, bandages, or dressings, or combinations thereof.Alternatively, the composition may be in the form of a spray, aerosol,solution, emulsion, nanosphere, microcapsule, nanocapsule, as well asother topical or transdermal forms known in the art. In a preferredembodiment, the invention is a gel, a lotion, or a cream. In a mostpreferred embodiment, the invention is a non-occlusive gel. Gels aresemisolid, suspension-type systems. Single-phase gels comprisemacromolecules (polymers) distributed substantially uniformly throughoutthe carrier liquid, which is typically aqueous. However, gels preferablycomprise alcohol and, optionally, oil. Preferred polymers, also known asgelling agents, are crosslinked acrylic acid polymers, polyethyleneoxides, polyoxyethylene-polyoxypropylene copolymers andpolyvinylalcohol; cellulosic polymers (hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, methyl cellulose); gums such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixingor stirring, or combinations thereof.

The compositions of the present invention may be manufactured byconventional techniques of drug formulation, particularly topical andtransdermal drug formulation, which are within the skill of the art.Such techniques are disclosed in “Encyclopedia of PharmaceuticalTechnology, 2^(nd) Ed., edited by I. Swarbrick and J. C. Boylan, MarcelDekker, Inc., 2002, the content of which is incorporated herein byreference.

The invention provides a composition for the transdermal administrationof oxybutynin which is useful in a variety of contexts, as will bereadily appreciated by those skilled in the art. For example, oxybutyninhas been indicated for the treatment of hyperactivity of the detrusormuscle (over activity of the bladder muscle) with frequent urge tourinate, increased urination during the night, urgent urination,involuntary urination with or without the urge to urinate(incontinence), painful or difficult urination. Generally, although notnecessarily, these disorders are caused by a neurogenic bladder. See,Guittard et al., U.S. Pat. No. 5,674,895, the content of which isincorporated herein by reference. In addition, oxybutynin may treatother conditions and disorders that are responsive to transdermaladministration of oxybutynin, such as detrusor hyperreflexia anddetrusor instability. Accordingly, in another aspect of the invention, amethod is provided for the treatment of overactive bladder or urge andurinary incontinence in a subject, comprising administering to a subjectin need thereof, a topical or transdermal composition of the presentinvention. Advantageously, the method of the invention provides a steadyplasma concentration of oxybutynin to a subject administered with thecomposition as well as reduces peak plasma concentrations of oxybutyninand lowers a number of incidences and/or intensities ofoxybutynin-associated side effects. Preferably, the method provides asustained transdermal oxybutynin flux allowing therapeutic levels ofoxybutynin for at least 24 hours. More preferably, the method provides asustained transdermal oxybutynin flux allowing therapeutic levels ofoxybutynin for at least 48 hours. Most preferably, the method provides asustained transdermal oxybutynin flux allowing therapeutic levels ofoxybutynin for at least 72 hours. Thus, the composition only needs to beadministrated every once a day, every other day, every third day ortwice per week.

EXAMPLES

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those skilled in the art in light of the present disclosureand the accompanying claims.

Example 1

A gel composed by oxybutynin free base 1 w/w to 5% w/w, anhydrousethanol 45% w/w to 75% w/w, diethylene glycol monoethyl ether 1% w/w to15% w/w, propylene glycol 1% w/w to 30% w/w, hydroxypropylcellulose(KLUCEL™ HF Pharm) 0.5% w/w to 2% w/w, hydrochloric acid HCl q. ad. forpH 4 to 9, and purified water q. ad. for 100% w/w, was prepared bydissolving the oxybutynin free base in the ethanol/propyleneglycol/diethylene glycol monoethyl ether mixture. Purified water wasthen added and pH adjusted to the target with hydrochloric acidsolution. Hydroxypropylcellulose was then thoroughly dispersed in thehydro-alcoholic solution under mechanical stirring at room temperatureat a suitable speed ensuring good homogenization of the formulationwhile avoiding lumps formation and air entrapment until completeswelling.

Example 2

A gel composed by oxybutynin free base 3% w/w, anhydrous ethanol 50%w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 15% w/w,hydroxypropylcellulose (KLUCEL™ HF Pharm) 1.5% w/w, hydrochloric acidHCl q. ad. for pH 7 to 8, and purified water q. ad. for 100% w/w, wasprepared according to manufacturing process described in Example 1.

Example 3

A gel composed by oxybutynin free base 3% w/w, ethanol 96% w/w˜55% w/w,diethylene glycol monoethyl ether 2.5% w/w, propylene glycol 20% w/w,hydroxypropylcellulose (KLUCEL™ HF Pharm) 1.5% w/w, butylhydroxytoluene(BHT) 0.05% w/w, hydrochloric acid HCl q. ad. for pH 7 to 8, andpurified water q. ad. for 100% w/w, was prepared according tomanufacturing process described in Example 1, wherein BHT is added tothe ethanol/propylene glycol/diethylene glycol monoethyl ether mixture.

Example 4

In vitro study was conducted to determine the permeability profile ofoxybutynin in human surgically excised skin using the oxybutyninformulation of Example 3 above, as compared with a marketed oxybutyningel product (GELNIQUE®, Watson Laboratories, Inc.). Each formulation wastested in 6 replicates on frozen human skin (one single skin donor).Overall, twelve skin samples were used, which were processed and slicedprior to use. The thickness of each skin sample was measured with amicrometer. The skin samples were then mounted on vertical glass Franzdiffusion cells with a receptor compartment of 7.39-7.78 mL, a donorcompartment of 3 mL and a diffusion area of 1.77 cm². Phosphate bufferedsaline (PBS) at pH 7.4, with addition of 2% w/v oleyl ether ofpolyoxyethylene glycol (Brij® 98) was used as the receptor solution, andmaintained at 35° C. during the whole study, under constant stirring(600 rpm). The study was performed by using a Microette® autosampler.After 2 hours pre-incubation of the skin samples with the receptorsolution, and integrity assessment by evaporimetry (measurement of transepidermal water loss, TEWL), about 10 mg (5.6 mg/cm²) of theformulations were applied with the tip of a plastic syringe plunger andgently spread over the skin diffusion surface. Diffusion of the drug wasallowed under non-occluded conditions during 24 hours. Receptor solutionsamples (1.2 mL) were automatically removed at 9-14-19-24 hours (after0.8 mL receptor compartment priming). The samples were collected in 2 mLHPLC amber glass vials pre-sealed with septum crimp-caps previouslyfilled with 10 μL of a solution of trifluoroacetic acid (TFA) 10%. Thensamples were transferred into Eppendorf microtubes and centrifuged(14500 rpm during 10 min). Supernatant (0.9 mL) were then transferred ina 2 mL HPLC amber glass vial. Analysis of the samples was performed byappropriate HPLC method. The results of this study are presented in FIG.1 and FIG. 2. At same drug loading, i.e. 5.8 mg gel/cm² skin, theformulation of Example 3 delivers significantly 2.3-fold more oxybutyninthrough the skin than GELNIQUE®, respectively 2.7 μg/cm² and 1.2 μg/cm²in 24 hours (p=0.02). Considering these in vitro data and assuming samepattern in vivo, we could conclude that application of 0.45 g of theformulation of Example 3 should be equivalent to application of 1 g ofGELNIQUE®.

Example 5

A gel composed by oxybutynin free base 3% w/w, anhydrous ethanol 30%w/w, isopropanol 20% w/w, diethylene glycol monoethyl ether 2.5% w/w,propylene glycol 15% w/w, hydroxypropylcellulose (KLUCEL™ HF Pharm) 1.5%w/w, hydrochloric acid HCl q. ad. for pH 7 to 8, and purified water q.ad. for 100% w/w, was prepared according to manufacturing processdescribed in Example 1 wherein isopropanol is added to theethanol/propylene glycol/diethylene glycol monoethyl ether mixture.

Example 6

A gel composed by oxybutynin free base 3% w/w, anhydrous ethanol 30%w/w, isopropanol 20% w/w, diethylene glycol monoethyl ether 2.5% w/w,polyethylene glycol 600 10% w/w, hydroxypropylcellulose (KLUCEL™ MFPharm) 1.5% w/w, hydrochloric acid HCl q. ad. for pH 6.5 to 7.5, andpurified water q. ad. for 100% w/w, was prepared according tomanufacturing process described in Example 1, wherein propylene glycolis substituted by polyethylene glycol 600.

Example 7

A gel composed by oxybutynin hydrochloride 10% w/w, anhydrous ethanol60% w/w, diethylene glycol monoethyl ether 2.5% w/w, propylene glycol2.5% w/w, hydroxypropylcellulose (KLUCEL™ MF Pharm) 2% w/w,butylhydroxytoluene (BHT) 0.05% w/w, sodium hydroxide NaOH q. ad. for pH4 to 6, and purified water q. ad. for 100% w/w, was prepared bydissolving the oxybutynin hydrochloride in the ethanol/propyleneglycol/diethylene glycol monoethyl ether/water mixture. pH was thenadjusted to the target with sodium hydroxide solution.Hydroxypropylcellulose was then thoroughly dispersed in thehydro-alcoholic solution under mechanical stirring at room temperatureat a suitable speed ensuring good homogenization of the formulationwhile avoiding lumps formation and air entrapment until completeswelling.

Example 8

A gel composed by oxybutynin hydrochloride 10% w/w, anhydrous ethanol60% w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 10%w/w, hydroxypropylcellulose (KLUCEL™ MF Pharm) 2% w/w,butylhydroxytoluene (BHT) 0.05% w/w, sodium hydroxide NaOH q. ad. for pH4 to 6, and purified water q. ad. for 100% w/w, was prepared accordingto manufacturing process described in Example 7.

Example 9

In vitro study was conducted to determine the permeability profile ofoxybutynin in pig ear skin using the oxybutynin formulations of Example7 and Example 8 above, as compared with a marketed oxybutynin gelproduct (GELNIQUE®, Watson Laboratories, Inc.). Each formulation wastested in 4 replicates (4 donors randomly assigned so that eachformulation is tested once on each skin sample). Procedure is the sameas those described above in Example 4. The results of this study arepresented in FIG. 3 and FIG. 4. At same drug loading, i.e. about 5.8 mggel/cm² skin, the two formulations of Example 7 and Example 8 areequivalent to GELNIQUE®.

Example 10

A gel composed by oxybutynin hydrochloride 10% w/w, anhydrous ethanol60% w/w, diethylene glycol monoethyl ether 5 w/w, propylene glycol 5%w/w, hydroxypropylcellulose (KLUCEL™ MF Pharm) 2% w/w,butylhydroxytoluene (BHT) 0.05% w/w, sodium hydroxide NaOH q. ad. for pH4 to 6, and purified water q. ad. for 100% w/w, was prepared accordingto manufacturing process described in Example 7.

Example 11

A gel composed by oxybutynin hydrochloride 10% w/w, anhydrous ethanol60% w/w, diethylene glycol monoethyl ether 1% w/w, propylene glycol 1%w/w, hydroxypropylcellulose (KLUCEL™ MF Pharm) 2% w/w,butylhydroxytoluene (BHT) 0.05% w/w, sodium hydroxide NaOH q. ad. for pH4 to 6, and purified water q. ad. for 100% w/w, was prepared accordingto manufacturing process described in Example 7.

Example 12

A gel composed by oxybutynin hydrochloride 10% w/w, anhydrous ethanol60% w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 2.5%w/w, hydroxypropylcellulose (KLUCEL™ MF Pharm) 2.00% w/w,butylhydroxytoluene (BHT) 0.05% w/w, sodium hydroxide NaOH q. ad. for pH4 to 6, and purified water q. ad. for 100% w/w, was prepared accordingto manufacturing process described in Example 7.

Example 13 Comparative

A gel composed by oxybutynin hydrochloride 10% w/w, anhydrous ethanol60% w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 6%w/w, tetradecanol (myristyl alcohol) 1% w/w, hydroxypropylcellulose(KLUCEL™ MF Pharm) 1.5 w/w, butylhydroxytoluene (BHT) 0.05% w/w, sodiumhydroxide NaOH q. ad. for pH 4 to 6, and purified water q. ad. for 100%w/w, was prepared according to manufacturing process described inExample 7.

Example 14 Comparative

A gel composed by oxybutynin hydrochloride 10% w/w, anhydrous ethanol60% w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 6%w/w, dodecanol (lauryl alcohol) 1% w/w, hydroxypropylcellulose (KLUCEL™MF Pharm) 1.5% w/w, butylhydroxytoluene (BHT) 0.05% w/w, sodiumhydroxide NaOH q. ad. for pH 4 to 6, and purified water q. ad. for 100%w/w, was prepared according to manufacturing process described inExample 7.

Example 15

In vitro study was conducted to determine the permeability profile ofoxybutynin in pig ear skin using the oxybutynin formulations of Example13 and Example 14 above, as compared with a marketed oxybutynin gelproduct (GELNIQUE®, Watson Laboratories, Inc.). Each formulation wastested in 4 replicates. Procedure is the same as those described abovein Example 9. The results of this study are presented in FIG. 5 and FIG.6. At same drug loading, i.e. about 5.8 mg gel/cm² skin, the twoformulations of Example 13 and Example 14 are equivalent to GELNIQUE®.Therefore addition of long-chain fatty alcohols to a composition of thepresent invention neither improves nor impairs the skin penetration ofoxybutynin.

Example 16

A gel composed by oxybutynin free base 3% w/w, anhydrous ethanol 58.1%w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 6% w/w,hydroxypropylcellulose (KLUCEL™ HF Pharm) 2.00% w/w, hydrochloric acidHCl q. ad. for pH 7 to 7.5, and purified water q. ad. for 100% w/w, wasprepared according to manufacturing process described in Example 1.

Example 17 Comparative

A gel composed by oxybutynin free base 3% w/w, anhydrous ethanol 58.1%w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 6% w/w,dodecanol (lauryl alcohol) 1%, hydroxypropylcellulose (KLUCEL™ HF Pharm)2% w/w, hydrochloric acid HCl q. ad. for pH 7 to 7.5, and purified waterq. ad. for 100% w/w, was prepared according to manufacturing processdescribed in Example 1.

Example 18 Comparative

A gel composed by oxybutynin free base 3% w/w, anhydrous ethanol 58.1%w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 6% w/w,oleyl alcohol 1%, hydroxypropylcellulose (KLUCEL™ HF Pharm) 2% w/w,hydrochloric acid HCl q. ad. for pH 7 to 7.5, and purified water q. ad.for 100% w/w, was prepared according to manufacturing process describedin Example 1.

Example 19

In vitro study was conducted to determine the permeability profile ofoxybutynin in pig ear skin using the oxybutynin formulations out of thescope of the present invention of Example 17 and Example 18 above, ascompared with oxybutynin formulation of the present invention of Example16. Each formulation was tested in 4 replicates. Procedure is the sameas those described above in Example 9 except that about 50 mg offormulations were applied on each skin sample. The results of this studyare presented in FIG. 7 and FIG. 8. At same drug loading, i.e. about 30mg gel/cm² skin, the two formulations of Example 16 and Example 17 areequivalent to the formulations of Example 16. Therefore addition oflong-chain fatty alcohols to a composition of the present inventionneither improves nor impairs the skin penetration of oxybutynin.

Example 20

A gel composed by oxybutynin free base 5% w/w, anhydrous ethanol 51.66%w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 6% w/w,hydroxypropylcellulose (KLUCEL™ HF Pharm) 2% w/w, hydrochloric acid HClq. ad. for pH 7 to 7.5, and purified water q. ad. for 100% w/w, wasprepared according to manufacturing process described in Example 1.

Example 21 Comparative

A gel composed by oxybutynin free base 5% w/w, anhydrous ethanol 51.66%w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 6% w/w,glycerol monolaurate 5% w/w, hydroxypropylcellulose (KLUCEL™ HF Pharm)2% w/w, hydrochloric acid HCl q. ad. for pH 7 to 7.5, and purified waterq. ad. for 100% w/w, was prepared according to manufacturing processdescribed in Example 1.

Example 22 Comparative

A gel composed by oxybutynin free base 5% w/w, anhydrous ethanol 51.66%w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 6% w/w,propylene glycol monolaurate 5% w/w, hydroxypropylcellulose (KLUCEL™ HFPharm) 2% w/w, hydrochloric acid HCl q. ad. for pH 7 to 7.5, andpurified water q. ad. for 100% w/w, was prepared according tomanufacturing process described in Example 1.

Example 23

In vitro study was conducted to determine the permeability profile ofoxybutynin in pig ear skin using the oxybutynin formulations out of thescope of the present invention of Example 21 and Example 22 above, ascompared with oxybutynin formulation of the present invention of Example20. Each formulation was tested in 4 replicates. Procedure is the sameas those described above in Example 19. The results of this study arepresented in FIG. 9 and FIG. 10. At same drug loading, i.e. about 30 mggel/cm² skin, the two comparative formulations of Example 20 and Example21 are equivalent to the formulations of Example 20. Therefore additionof long-chain fatty esters to a composition of the present inventiondoes not improve the skin penetration of oxybutynin.

Example 24 Comparative

A gel composed by oxybutynin free base 3% w/w, anhydrous ethanol 58.1%w/w, diethylene glycol monoethyl ether 5% w/w, propylene glycol 6% w/w,lauric acid 1%, hydroxypropylcellulose (KLUCEL™ HF Pharm) 2% w/w,hydrochloric acid HCl q. ad. for pH 7 to 7.5, and purified water q. ad.for 100% w/w, was prepared according to manufacturing process describedin Example 1.

Example 25

In vitro study was conducted to determine the permeability profile ofoxybutynin in pig ear skin using the oxybutynin formulations out of thescope of the present invention of Example 17, Example 18 and Example 24above. Each formulation was tested in 4 replicates. Procedure is thesame as those described above in Example 19. The results of this studyare presented in FIG. 11 and FIG. 12. At same drug loading, i.e. about30 mg gel/cm² skin, the three formulations of Example 17, Example 18 andcomparative Example 24 are equivalent to the formulations of Example 20.Therefore addition of long-chain fatty acids to a composition of thepresent invention does not improve the skin penetration of oxybutynin.

Example 26 Pilot Pharmacokinetic Study of an Oxybutynin Gel Formulationof the Present Invention in Healthy Volunteers

In vivo study was conducted by a qualified investigator to determine thepharmacokinetics of oxybutynin in healthy human volunteers. The studywas a single-center, multiple-dose, open-label study during which theoxybutynin formulation of the present invention of Example 3 above wastested. This study was planned and performed in accordance with theDeclaration of Helsinki in its version of Somerset West, 1996, and inaccordance with the EU Clinical Trial Directive 2001/20/EC and relevantguidances (“Note for Guidance on Good Clinical Practice”,CPMP/ICH/135/95 of Jan. 17, 1997; “Note for Guidance on theInvestigation of Bioavailability and Bioequivalence”,CPMP/EWP/QWP/1401/98; “Note for Guidance on modified release oral andtransdermal dosage forms: Section II”, CPMP/EWP/280/96). Treatmentconsisted in multiple doses of 2.8 g of gel per day (corresponding to 84mg oxybutynin per day) administered each morning for 7 consecutive days.The gel was distributed over a skin area of 700 cm² on the abdomen.

58 non-smoking males and females (including 25-40 women), aged 18 to 55,white, physically and mentally healthy as confirmed by an interview,medical history, clinical examination and having given written informedconsent, enrolled in this study. Summary data on study population arepresented in Table 5 herein. 54 subjects completed the study. Bloodsampling was performed on Day 1 at initiation of the study (H0), andthen on Day 7 (H0+144; H0+146; H0+148; H0+152; H0+156), Day 8 (H0+160;H0+164; H0+168), Day 9 (H0+192), Day 10 (H0+216), Day 11 (H0+240) andDay 12 (H0+264). Blood samples were then processed and analyzed byLC-MS-MS method (LLOQ set to 50 ng/ml). Criteria considered forevaluation were Pharmacokinetics (oxybutynin and N-desethyloxybutynin),area under the concentration-time curve (AUC_(T)), highest concentrationdetermined in the measuring interval (C_(max)), and adverse events andvital signs. Summary results of this study are presented in Table 6 andin Table 7 herein.

TABLE 5 Pilot pharmacokinetic study of an oxybutynin gel formulation ofthe present invention in healthy volunteers: demographic data, safetypopulation Body Ethnic Age weight Height BMI Sex origin Stat. [years][kg] [cm] [kg/m²] female white, N 58 58 58 58 and male N = 58 Mean 36.172.9 174.8 23.74 SD 8.3 11.9 9.2 2.38 CV 23.1 16.3 5.3 10.02 Minimum 2248 156 19.2 Median 34.0 74.0 176.0 24.15 Maximum 52 100 199 27.0 female,white, N 32 32 32 32 N = 32 N = 32 Mean 34.5 65.4 168.5 22.99 SD 8.9 9.26.2 2.54 CV 25.9 14.1 3.7 11.04 Minimum 22 48 156 19.2 Median 31.0 63.0168.0 22.20 Maximum 51 92 185 27.0 males white, N 26 26 26 26 N = 26 N =26 Mean 38.2 82.2 182.5 24.67 SD 7.2 7.5 5.7 1.82 CV 18.9 9.1 3.1 7.36Minimum 27 66 176 20.6 Median 37.0 83.0 181.5 25.20 Maximum 52 100 19926.9

TABLE 6 Pilot pharmacokinetic study of an oxybutynin gel formulation ofthe present invention in healthy volunteers: summary kinetic variablesfor oxybutynin Variable Statistics Results AUC_(T) N 54 [ng/ml * h] Mean156.0676 SD 62.7989 GeoM 143.6709 G_CV 44.4 C_(av) N 54 [ng/ml] Mean6.5028 SD 2.6166 GeoM 5.9863 G_CV 44.4 C_(max) N 54 [ng/ml] Mean 9.7444SD 5.1062 GeoM 8.6067 G_CV 54.7 C_(min) N 54 [ng/ml] Mean 4.3767 SD1.8940 GeoM 4.0096 G_CV 44.5 PTF N 54 Mean 0.77 SD 0.31 GeoM 0.71 G_CV41.7 R N 54 (coefficient Min −1.000 of correlation) Med −0.994 Max−0.863 t_(1/2) N 54 [h] Mean 29.18 SD 8.35 GeoM 28.16 G_CV 26.7 t_(max)N 54 [h] Mean 6.67 SD 6.20 CV 93.0 Min 0.00 Med 4.00 Max 24.00 T_(cav) N54 [h] Mean 10.42 SD 1.69 CV 16.2 Min 7.24 Med 10.27 Max 15.05 AUC: areaunder the concentration time curve; C_(AV): average steady stateconcentration; C_(max): highest concentration determined in themeasuring interval; C_(min): lowest concentration determined in themeasuring interval; PTF: peak trough fluctuation; t_(1/2): half-life;t_(max): time at which Cmax occurs; T_(Cav): time period ofconcentration being above Cav; N: number of subjects; SD: standarddeviation; GeoM: geometric mean; G_CV: geometric coefficient of variance(%) of geometric mean.

TABLE 7 Pilot pharmacokinetic study of an oxybutynin gel formulation ofthe present invention in healthy volunteers: summary kinetic variablesfor N-Desethyloxybutynin Variable Statistics Results AUC_(T) N 54[ng/ml * h] Mean 157.7218 SD 88.6001 GeoM 137.7699 G_CV 55.3 C_(av) N 54[ng/ml] Mean 6.5717 SD 3.6917 GeoM 5.7404 G_CV 55.3 C_(max) N 54 [ng/ml]Mean 8.9495 SD 5.3402 GeoM 7.6858 G_CV 59.2 C_(min) N 54 [ng/ml] Mean4.6255 SD 2.6520 GeoM 4.0281 G_CV 56.0 PTF N 54 Mean 0.64 SD 0.23 GeoM0.59 G_CV 40.3 R N 54 (coefficient Min −1.000 of correlation) Med −0.996Max −0.872 t_(1/2) N 54 [h] Mean 31.17 SD 8.42 GeoM 30.11 G_CV 27.0t_(max) N 54 [h] Mean 7.97 SD 4.44 Min 0.00 Med 8.00 Max 24.00 T_(Cav) N54 [h] Mean 10.79 SD 1.55 Min 6.96 Med 10.63 Max 13.61 AUC: area underthe concentration time curve; C_(AV): average steady state concentrationC_(max): highest concentration determined in the measuring interval;C_(min): lowest concentration determined in the measuring interval; PTF:peak trough fluctuation; t_(1/2): half-life; t_(max): time at which Cmaxoccurs; T_(Cav): time period of concentration being above Cav; N: numberof subjects; SD: standard deviation; GeoM: geometric mean; G_CV:geometric coefficient of variance (%) of geometric mean.

TABLE 8 Pilot pharmacokinetic study of an oxybutynin gel formulation ofthe present invention in healthy volunteers: number and percent ofsubjects (N = 56) reporting adverse events occurring after 1^(st)administration Total number (%) of subjects with AE 28 (50%) Cardiacdisorders 0 (0%) Tachycardia 0 (0%) Eye disorders 3 (5%) Vision blurred2 (4%) Dry eye 1 (2%) Eye irritation 0 (0%) Gastrointestinal disorders10 (18%) Dry mouth  7 (13%) Nausea 3 (5%) Flatulence 2 (4%) Abdominaldistension 1 (2%) Vomiting 1 (2%) Abdominal pain 0 (0%) Abdominal painupper 1 (2%) Constipation 1 (2%) General disorders and administrationsite conditions  8 (14%) Fatigue 2 (4%) Application site erythema 1 (2%)Application site pruritus 1 (2%) Application site anaesthesia 0 (0%)Application site cold feeling 1 (2%) Application site exfollation 0 (0%)Application site irritation 1 (2%) Asthenia 1 (2%) Non-cardiac chestpain 1 (2%) Pyrexia 1 (2%) Infections and infestations 4 (7%)Nasopharyngltis 4 (7%) Cystitis 0 (0%) Gastroenteritis 0 (0%) Urinarytract infection 0 (0%) Injury, poisoning and procedural complications 1(2%) Skin laceration 0 (0%) Vessel puncture site paraesthesia 1 (2%)Metabolism and nutrition disorders 2 (4%) Anorexla 2 (4%)Musculoskeletal and connective tissue disorders 0 (0%) Myotonia 0 (0%)Nervous system disorders 12 (21%) Headache 11 (20%) Dizziness 1 (2%)Post-traumatic headache 0 (0%) Renal and urinary disorders 1 (2%)Micturition urgency 0 (0%) Pollakluria 1 (2%) Reproductive system andbreast disorders 1 (2%) Breast pain 0 (0%) Menstrual disorder 0 (0%)Metrorrhagla 1 (2%) Respiratory, thoracic and mediastinal disorders 2(4%) Oropharyngeal pain 2 (4%)

Plasmatic oxybutynin concentration reached a steady state after 6repeated doses. The average plasmatic concentration of oxybutynin was5.99 ng/ml. C_(max) was 8.61 ng/ml (geometric mean). T_(max), the timeat which the concentration of oxybutynin (C_(max)) peaks, occurred about4 hours (median) after application. The terminal half-life T_(1/2) was28.16 hours (geometric mean). See FIG. 13.

Plasmatic N-desethyloxybutynin concentration reached also steady stateafter 6 repeated doses. The average plasmatic concentration ofoxybutynin was 5.74 ng/ml. C_(max) was 7.69 ng/ml (geometric mean).T_(max), the time at which the concentration of oxybutynin (C_(max))peaks, occurred about 8 hours (median) after application. The terminalhalf-life T_(1/2) was 30.11 hours (geometric mean). See FIG. 14.

The majority of the reported adverse events (AEs) was classified asrelated to the study medication itself. The most often observed AE wasdry mouth (13% of subjects), reported as a common side-effect ofoxybutynin. The other common side-effects were reported infrequently (5%of subjects or less). The observed skin-tolerability of the treatmentwas good, with only eight subjects reporting mild skin reactions. Nosignificant changes in vital signs, electrocardiogram parameters,physical findings or in clinical laboratory variables were detected. Theresults are shown in Table 8 herein.

While the invention has been described and pointed out in detail withreference to operative embodiments thereof, it will be understood bythose skilled in the art that various changes, modifications,substitutions, and omissions can be made without departing from thespirit of the invention. It is intended therefore, that the inventionembrace those equivalents within the scope of the claims that follow.

1. A composition for transdermal or transmucosal administration ofoxybutynin comprising: an anti-cholinergic agent of oxybutynin in anamount between about 0.1 to 20% by weight of the composition; a deliveryvehicle which comprises a C2 to C4 alkanol, a polyalcohol, a monoalkylether of diethylene glycol, and water, present in relative amountssufficient to provide permeation enhancement of oxybutynin throughmammalian dermal or mucosal surfaces; wherein the composition issubstantially free of long-chain fatty alcohols, long-chain fatty acids,and long-chain fatty esters in order to avoid undesirable odor andirritation effects caused by such compounds during use of thecomposition.
 2. The composition of claim 1, wherein the oxybutynin ispresent as oxybutynin free base, as a pharmaceutically acceptable saltof oxybutynin, or as a mixture thereof.
 3. The composition of claim 2,wherein the pharmaceutically acceptable salt of oxybutynin is selectedfrom the group consisting of acetate, bitartrate, citrate, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, hydrobromide, hydrochloride, lactate, malate, maleate,mandelate, mesylate, methylnitrate, mucate, napsylate, nitrate, pamoate,pantothenate, phosphate, salicylate, stearate, succinate, sulfate,tannate and tartrate.
 4. The formulation of claim 1, wherein the alkanolis selected from the group consisting of ethanol, isopropanol,n-propanol, and mixtures thereof; wherein the polyalcohol is selectedfrom the group consisting of propylene glycol, dipropylene glycol,polyethylene glycol, glycerin, and mixtures thereof; and wherein themonoalkyl ether of diethylene glycol is selected from the groupconsisting of monomethyl ether of diethylene glycol, monoethyl ether ofdiethylene glycol, and mixtures thereof.
 5. The composition of claim 1,thither comprising at least one excipient selected from the groupconsisting of gelling agents, solvents, cosolvents, antimicrobials,preservatives, antioxidants, buffers, humectants, sequestering agents,moisturizers, emollients, film-forming agents, or permeation enhancers.6. The composition of claim 1 wherein the formulation is in the form ofa topical gel, lotion, foam, cream, spray, aerosol, ointment, emulsion,microemulsion, nanoemulsion, suspension, liposomal system, lacquer,patch, bandage, or occlusive dressing.
 7. The composition of claim 1,wherein oxybutynin is in combination with a secondary active agent forconcurrent administration.
 8. The composition according to claim 1wherein the alkanol is present in the delivery system in an amountbetween about 45 and 75% by weight of the composition; the polyalcoholis present in the delivery system in an amount between about 1 to 30% byweight of the composition; and the monoethyl ether of diethylene glycolis present in the delivery system in an amount between about 1 to 15% byweight of the composition.
 9. The composition according claim 1, whereinthe oxybutynin is present as oxybutynin free base in an amount betweenabout 1 to 5% by weight of the composition; and wherein the alkanol isethanol, isopropanol, or a mixture thereof in an amount between about 45and 60% by weight of the composition; the polyalcohol is propyleneglycol and is present in an amount between about 1 to 20% by weight ofthe composition; and the monoethyl ether of diethylene glycol is presentin an amount between about 1 to 5% by weight of the composition.
 10. Amethod for administering oxybutynin to a mammal in need thereof whichcomprises topically or transdermally administering to the skin or themucosa of a mammal a composition according to claim
 1. 11. The method ofclaim 10, wherein the mammal is a human and the oxybutynin isadministered for treating hyperactivity of the detrusor muscle withfrequent urge to urinate, increased urination during the night, urgenturination, involuntary urination with or without the urge to urinate,painful or difficult urination, detrusor hyperreflexia and detrusorinstability.
 12. The method of claim 11, wherein a daily dose ofoxybutynin of between about 40 and about 100 mg is administered upon theabdomen, shoulder, arm, or thigh of the subject.